DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on September 5, 2025.
Currently, claims 1-18 are pending in the instant application. Claims 5-7 and 10-18 are withdrawn from further consideration as being drawn to nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 1-4 and 8-9 are under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
Claims 1-4 and 8-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Arechavala-Gomeza et al. in view of Carroll, Zhang, and Bozzoni et al. for the reasons as set forth in the Office action mailed on June 5, 2025 and for the reasons set forth below.
Applicant's arguments filed on September 5, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because the cited art individually or in combination do not teach the results disclosed in the instant specification’s Tables 4, 7, and 9, Example 5, and Figures 16 and 26A, wherein the instantly claimed gRNA of SEQ ID NO:67 providing 13% modification and the gRNA of SEQ ID NO:680 providing 11.9% modification resulted in “greater activity than other gRNAs targeting exon 51”, wherein the intron 50-targeting SEQ ID NO:65 is “a fair comparison” because it deletes exon 51. In response, it is noted that the instantly rejected claims are merely directed to a composition, wherein SEQ ID NO:67 introduces a frameshift mutation in exon 51 and SEQ ID NO:680 deletes exon 51. In addition, claims 8-9 are directed to a composition with the intended use “for genome editing in a muscle of a subject”. As written, the rejected composition claims do not require any specific level (e.g., 13%, 11.9%) of modification in dystrophin exon 51, nor do they require a certain level of “off-target activity” or “cytotoxicity”. Hence, the features pointed out by applicant are not required to be taught by the cited prior art, thus applicant’s argument that the cited art does not teach the activity levels disclosed in the specification is not found persuasive to show the asserted nonobviousness of the rejected claims. As such, applicant’s argument that one of ordinary skill in the art would not have predicted the activity of the claimed gRNAs pertaining to the modification levels, “incredibly minimal off-target activity”, and “low cytotoxicity” is not sufficient to support the asserted nonobviousness of the rejected claims, which do not require the features relied on by applicant.
It is noted that Table 6 of the specification filed on September 30, 2020 expressly discloses that the “Target” of SEQ ID NO:65 (DCR2) is “Intron 50”. As such, SEQ ID NO:65 is not targeted to exon 51. Now, it is noted that SEQ ID NO:66 or SEQ ID NO:679 (“DCR2”) is also targeted to “Intron 50” and resulted in the deletion of exon 51 with 10.3% modification level. Moreover, SEQ ID NO:69 or SEQ ID NO:630 (“DCR5”) is targeted to “Intron 51” and resulted in the deletion of exon 51 with 12.4% modification level. That is, even if only the final result of exon 51 modification should be considered regardless the actual target sequence’s location (e.g., intron 50, intron 51), which appears to applicant’s position, the 11.9% exon 51 deletion provided by SEQ ID NO:680 (“DCR4”) does not amount to be a “greater” level with a statistical significance when compared to other sequences that deleted exon 51. As for the activity of SEQ ID NO:67 claimed to introduce a frameshift mutation in exon 51, it is noted that there is no other sequence that provided such mutation. That is, SEQ ID NO:67 is the only gRNA disclosed to have the required function. Hence, applicant’s asserted “greater activity” provided by SEQ ID NO:67 “than other gRNAs targeting exon 51” is not supported by the specification.
Applicant argues that Zhang teaches that off-target activity is “common” with gRNAs and demonstrates “significant off-target activity” in Figure 65, wherein one skilled in the art would not have predicted the minimal off-target activity of SEQ ID NO:67 as shown in Table 4. In response, it is noted that Zhang expressly taught that “off-targeting could easily be avoided by a systemic blast of the designed spacers.” See paragraph 0394. Furthermore, Zhang’ Figure 65 expressly demonstrates that only gRNAs targeting two genes, CHD8 and SHANK3 showed off-target predictions out of a total of nine different targets that are tested with three different gRNAs. That is, the majority of gRNAs tested by Zhang did not show off-target effects. Hence, the off-target activity against one non-target gene, STRIP1, in cells transfected with SEQ ID NO:67 would have been reasonably predicted by a person of ordinary skill in the art especially in view of Zhang’s express teaching that “off-targeting could easily be avoided by a systemic blast of the designed spacers.”
Applicant asserts that the examiner used improper hindsight “with present-day knowledge”, whereas the knowledge pertaining to designing effective gRNAs “was not routine or understood with an expectation of success at the effective filing date of the present application (June 2014).” In response, it is noted that effective gRNA design having no detectable off-target effects was known in the prior art, not just “present-day knowledge”, as evidenced by the plurality of gRNAs showing intended activity against the intended target without off-target effects as shown in Figure 65. It is unclear whether applicant attempts to state on the record that the instant co-inventors did not utilize the prior art-recognized gRNA identification/design methodology for Cas9 by identifying the NGG PAM sequence, especially the 5’-(N)20NGG sequence, within the intended target as taught by Zhang. If such is the case, that is, if the instant co-inventors designed the instantly claimed SEQ ID NOs:67 and 680 by unconventional, novel, unknown methodology, applicant is invited to point out the specific passage in the specification that the gRNA design methodology that was not taught and utilized by Zhang was used in the instant application so as to objectively support that the effective gRNA design was indeed not known in the prior art before June, 5, 2014. Absent such objective evidence, it is noted that the objective, factual evidence on the record in the instant application does support that effective target sequence-specific gRNA design was expressly taught, known, and utilized in the prior art as evidenced by Zhang’ teachings as explained in detail in the last Office action. Note that “arguments presented by applicant cannot take the place of factually supported objective evidence.” See MPEP §2145.
In view of the foregoing, this rejection is maintained.
Double Patenting
Claims 1-4 and 8-9 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-20 of U.S. Patent No. 12,037,598 B2 in view of Arechavala-Gomeza et al., Zhang, and Bozzoni et al. for the reasons as set forth in the Office action mailed on June 5, 2025 and for the reasons set forth below.
Applicant's arguments filed on September 5, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘598 patent contains “no enabling data for dystrophin”. In response, applicant’s attention is directed to the fact that an enabling disclosure is not legally required for rendering claims obvious under NSDP rejection. Furthermore, the instantly rejected claims are mere composition claims, not a method of using a gRNA or a method of treating a condition in a subject comprising administering the claimed gRNA. Hence, it is unclear why the ‘598 patent is required to disclose an enabling disclosure.
Applicant argues that the ‘598 patent does not disclose the instantly claimed SEQ ID NOs. In response, it is noted that the prima facie obviousness of the instantly claimed SEQ ID NOs is established over the combined teachings of the secondary references cited in the instant rejection.
Applicant argues that the cited references do not teach “their surprising activity and specificity.” In response, the alleged “surprising” activity is not a claimed feature and furthermore, the specificity (e.g., no or minimal off-target activity) by multiple gRNAs designed in accordance with Zhang’s disclosure was already demonstrated by Zhang in Figure 65, wherein Zhang also taught that “off-targeting could easily be avoided by a systemic blast of the designed spacers.” Hence, the one off-target (STRIP1) modified by SEQ ID NO:67 is not deemed “surprising”.
In view of the foregoing, this rejection is maintained.
Claims 1-4 and 8-9 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-20 of U.S. Patent No. 12,146,151 B2 in view of Arechavala-Gomeza et al., Zhang, and Bozzoni et al. for the reasons as set forth in the Office action mailed on June 5, 2025 and for the reasons set forth below.
Applicant's arguments filed on September 5, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘151 patent contains “no enabling data for dystrophin”. In response, applicant’s attention is directed to the fact that an enabling disclosure is not legally required for rendering claims obvious under NSDP rejection. Furthermore, the instantly rejected claims are mere composition claims, not a method of using a gRNA or a method of treating a condition in a subject comprising administering the claimed gRNA. Hence, it is unclear why the ‘151 patent is required to disclose an enabling disclosure.
Applicant argues that the ‘151 patent does not disclose the instantly claimed SEQ ID NOs. In response, it is noted that the prima facie obviousness of the instantly claimed SEQ ID NOs is established over the combined teachings of the secondary references cited in the instant rejection.
Applicant argues that the cited references do not teach “their surprising activity and specificity.” In response, the alleged “surprising” activity is not a claimed feature and furthermore, the specificity (e.g., no or minimal off-target activity) by multiple gRNAs designed in accordance with Zhang’s disclosure was already demonstrated by Zhang in Figure 65, wherein Zhang also taught that “off-targeting could easily be avoided by a systemic blast of the designed spacers.” Hence, the one off-target (STRIP1) modified by SEQ ID NO:67 is not deemed “surprising”.
In view of the foregoing, this rejection is maintained.
Claims 1-4 and 8-9 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8-10, 13-14, 19-20, 23-25, 28, 30-31, 36, 38, 40, and 43 of copending Application No. 17/921,336 in view of Arechavala-Gomeza et al., Zhang, and Bozzoni et al. for the reasons as set forth in the Office action mailed on June 5, 2025 because applicant did not provide any substantial rebuttal arguments addressing the supposed errors of this rejection.
Claims 1-4 and 8-9 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-31, 41-43, 47-48, and 51 of copending Application No. 18/840,829 in view of Arechavala-Gomeza et al., Zhang, and Bozzoni et al. for the reasons as set forth in the Office action mailed on June 5, 2025 because applicant did not provide any substantial rebuttal arguments addressing the supposed errors of this rejection.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635